This invention relates to antigen markers characteristic of tumors, antibodies to those markers, and immunoassays based on those markers. It also relates to vaccines and to tumor imaging and immunotherapy using tumor specific reagents.
When exposed to foreign substances, the immune system produces proteins, known as antibodies, which specifically bind to those foreign substances. The substances which trigger antibody production, and to which antibodies bind, are known as antigens.
Antigens present on the surface of cells may serve as cell-surface markers, and the presence of such markers can be detected by antibodies that are specific for them. In that way antibodies are used to detect the presence of cells. Since cells can be characterized by the markers they possess, it is possible to identify cell types using antibodies.
Many cell surface markers are glycosylated proteins (glycoproteins). Notable among the glycoproteins are mucin-type glycoproteins, which are large molecules with a high proportion of carbohydrate chains that are O-linked through N-acetylgalactosamine to serine and/or threonine in the protein core.
There are various reports of antigens, some of which are mucin-type glycoproteins, that appear on the surfaces of tumor cells but not on the surfaces of normal cells of the same host. There are also various disclosures related to the use of such tumor specific antigens and antibodies to these antigens.
For example, there is a significant body of literature reporting studies on a sialomucin known as epiglycanin, which is found at the surface of the mouse carcinoma cell line TA3-Ha. Epiglycanin was first reported in 1972 by Codington et al., (1972) Biochemistry 11:2559-2564. Mild proteolysis of viable TA3-Ha ascites cells with TPCK-trypsin, followed by fractionation of the released peptides by gel exclusion chromatography, gave a peak of glycopeptide material of high molecular weight, and that material has been the subject of numerous subsequent studies: Codington et al., (1973) J. Nat'l Cancer Inst. 51:585-591; Slayter et al., (1973) J. Biol. Chem. 248:3405-3410; Codington et al., (1975) Biochemistry 14:855-859; Codington et al., (1979) J. Nat'l Cancer Instit. 63:153-162; Watkins et al., (1990) Carbohydr. Res. 213:185-200; Henningson et al., (1987) Cancer Immunol. Immunother. 25:231-241. Epiglycanin is generally characterized as having a molecular weight of 500,000, about 80% of which is carbohydrate, largely Gal.beta. (1.fwdarw.3) GalNAc side chains linked to serine or threonine residues in a polypeptide chain of about 1,300 amino acids. See, Van den Eijnden et al., (1979) J. Biol. Chem. 254:12153-12159. For reviews of this literature, see Codington et al., (1992) Glycobiology 2:173-180; and Haavik et al., (1992) Glycobiology 2:217-224.
Polyclonal antibodies to epiglycanin have been reported in Codington et al., (1984) J. Nat'l Cancer Instit. 73:1029-1038. Several monoclonal antibodies to epiglycanin have also been reported. Codington, U.S. Pat. No. 4,837,171; Haavik et al., (1992) Glycobiology 2(3):217-224. The polyclonal antibodies were found to react with a substance in peritoneal or pleural fluid and in sera of patients with metastatic cancer. Codington et al., (1984) J. Nat'l Cancer Inst. 73:1029-1038.
Other tumor specific markers have been reported.
Samuel et al., in U.S. Pat. No. 5,110,911, report an adenocarcinoma-derived antigen which is shed by human tumor cells. This glycoprotein, termed Thomsen-Friedenreich (TF) antigen, has a molecular weight greater than 1,000,000 and is characterized by a non-cryptic Gal.beta.(1.fwdarw.3)GalNAc epitope.
Kortright, in U.S. Pat. Nos. 4,708,930 and 4,743,543, reports a murine monoclonal antibody specific for an antigenic determinant on the surface or in the cytoplasm of human carcinoma cells and tissue. The antigenic determinant is designated "KC-4 antigen" and is said to appear in two forms, one having a molecular weight of 480,000-510,000 and the second having a molecular weight of 390,000-450,000. The KC-4 antigen was developed from human prostate adenocarcinoma.
Salem et al., in U.S. Pat. No. 4,921,789 report an antigen marker for human colorectal cancer, having a molecular weight of about 160,000. The antigen is said to be non-reactive with antibodies to certain other antigens.
O'Brien, in U.S. Pat. No. 4,921,790, reports a subunit of CA125 antigen, an antigen associated with cystadenocarcinoma of the ovary. The CA125 antigen has a molecular weight of about 40,000.
Kufe, in U.S. Pat. Nos. 4,963,484 and 5,053,489, reports identification (by recombinant methods) of a peptide determinant of the DF3 antigen from human breast carcinoma.
Chu et al., in U.S. Pat. No. 4,939,240, report a monoclonal antibody said to reduce the mass of a human breast tumor xenograft in a mouse.
Hellstrom et al., in U.S. Pat. No. 4,918,164, report a monoclonal anti-idiotypic antibody having an antigen combining site related to that of the p97 antigen of human melanoma.
Toth et al., in U.S. Pat. No. 4,914,021, report a monoclonal antibody specific for an antigen termed carcinoma or orosomucoid-related antigen (CORA). CORA is said to have a molecular weight of about 46,000-50,000, an isoelectric point of 3.0-3.5, and a carbohydrate content of 30% (by weight).
Yoshida, in U.S. Pat. No. 4,892,935, report an antibody to a human pulmonary carcinoma antigen which reacts with human squamous cell lung carcinoma but not with human small cell lung carcinoma.
Kjeldsen et al., (1988) Cancer Res. 48:2214-2220, report a breast carcinoma glycoprotein termed TAG-72.
Springer et al., (1988) Carbohydr. Res. 178:271-292, report T and Tn haptens in glycoproteins of human breast carcinoma.
Tjandra et al., (1988) Br. J. Surg. 75:811-817, report a breast carcinoma glycoprotein termed MSA.
Ishida et al., (1989) Tumor Biol. 10:12-22, report a breast carcinoma antigen termed MFGM.
Lan et al., (1985) Cancer Res. 45:305-310, report a pancreatic carcinoma antigen termed DU-PAN-2.
Hanisch et al., (1988) Carbohydr. Res. 178:29-47, report an ovarian carcinoma antigen termed CA125.
Hinoda et al., (1988) Cancer J. 42:653-658, report a lung carcinoma antigen termed YH206.